- Topoisomerase inhibitors are a critical class of chemotherapeutic agents that target enzymes essential for maintaining DNA topology during key cellular processes like replication and transcription. These drugs exploit the dependency of rapidly dividing cancer cells on topoisomerases, leading to the accumulation of DNA damage and ultimately, cell death.
- The two major classes of topoisomerases—topoisomerase I (TOP1) and topoisomerase II (TOP2)—are both targeted by distinct groups of inhibitors with well-established roles in cancer therapy.
- Topoisomerase I inhibitors function by stabilizing the enzyme-DNA complex after TOP1 has induced a transient single-strand break to relieve supercoiling. Under normal circumstances, TOP1 reseals the break after torsional stress is resolved. However, inhibitors such as camptothecin and its derivatives—topotecan and irinotecan—trap the enzyme in its cleaved state. This results in the accumulation of single-strand breaks that are converted into lethal double-strand breaks during DNA replication. Topotecan is commonly used for ovarian and small cell lung cancers, while irinotecan is a mainstay in colorectal cancer treatment regimens.
- Topoisomerase II inhibitors, by contrast, stabilize the double-strand break intermediates created by TOP2, preventing re-ligation and leading to persistent DNA breaks. These breaks are highly cytotoxic and activate cell death pathways. Etoposide and teniposide, both derived from podophyllotoxin, are widely used in treating testicular cancer, leukemias, and lymphomas. Another group of TOP2 inhibitors includes anthracyclines such as doxorubicin and daunorubicin, which not only inhibit TOP2 but also intercalate into DNA, contributing to their anticancer effects. These agents are especially effective against breast cancer and various hematological malignancies.
- Despite their efficacy, topoisomerase inhibitors are associated with significant clinical challenges. One major limitation is their dose-limiting toxicity, particularly bone marrow suppression and mucositis, which can compromise treatment adherence and patient quality of life. Additionally, prolonged exposure to TOP2 inhibitors has been linked to the development of secondary malignancies, including therapy-related acute myeloid leukemia (t-AML). Drug resistance is another hurdle, often arising from overexpression of efflux transporters like P-glycoprotein, mutations in topoisomerase genes, or enhanced DNA repair mechanisms that counteract drug-induced damage.
- To overcome these obstacles, recent research has focused on developing next-generation topoisomerase inhibitors with improved pharmacokinetic properties and reduced toxicity. For example, non-camptothecin TOP1 inhibitors like indenoisoquinolines are being explored in clinical trials. Novel strategies also include dual-function inhibitors that target both TOP1 and TOP2, or combine topoisomerase inhibition with other mechanisms, such as histone deacetylase inhibition. Targeted delivery systems, including liposomes and nanoparticles, are being developed to enhance tumor-specific drug accumulation while sparing healthy tissues.
